Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor involved in protecting cells from stresses. Under unstressed conditions, Nrf2 is bound to Keap1 (Kelch-like ECH-associated protein 1) that is an adaptor protein for ubiquitin E3 ligase and is constitutively degraded through the ubiquitin-proteasome pathway. Exposure to certain stresses, however, causes the modification of Keap1, which inhibits its binding to Nrf2. As a result, Nrf2 is accumulated in the nucleus and activates the expression of antioxidant proteins and detoxification enzymes to provide a defense mechanism. Mutations in either Nrf2 or Keap1 have been identified inpatients with, for example, some kind of lung cancer. These mutations cause loss of interaction between Keap1 and Nrf2, which makes tumor cells resistant to anticancer agents (Komatsu M. et al., Nat. Cell Biol. 2010, vol. 12, p. 213-23).
On the other hand, p62 is known as an adaptor molecule which is involved in selective autophagy. p62 can interact with the domain (aa309-624) of Keap1, containing the Nrf2-binding site. Thus, due to the p62 accumulation in cells by a deficiency in autophagy or an overexpression of p62, the binding between Keap1 and Nrf2 is competitively inhibited, resulting in the activation of the aforementioned defense mechanism by free Nrf2 (WO 2011/083637; Komatsu M. et al., Nat. Cell Biol. 2010, vol. 12, p. 213-23).
Aberrant accumulation of p62 has been observed in malignant tumors such as liver cancer or glioma. It has been suggested that increase in Keap1-p62 complex is advantageous for proliferation of malignant liver cancers. This means that the inhibition of their binding can be a target of cancer treatment.